The overall goal of our research is to investigate the chemical mechanisms of enzymatic reactions with an emphasis on those that could be targeted for drug therapy in the treatment of human disease. The general approach is to design, synthesize, and analyze the interactions of substrate analogues with a target enzyme to elucidate the catalytic mechanism of the enzymatic reaction. In the process of designing and analyzing these analogues, our aim is to identify potent inhibitors that may serve as drug candidates themselves or as leads in the design of drug candidates. The enzyme orotidine 5'- monophosphate decarboxylase (ODCase) is involved in the biosynthesis of uridine 5'-monophosphate (UMP), a nucleic acid building block, and thus represent a potential target for development of anti-tumor drugs. Substrate analogues will be synthesized to determine the structural features on the pyrimidine moiety that are important for binding, the contributions of functional groups on the phosphoribose groups to binding and catalysis, and the optimal relative positions of the pyrimidine and phosphoribose moieties. C-Nucleotide analogue will be synthesized and inhibition studies with ODCase completed. These studies will allow us to narrow down possible chemical mechanisms for the ODCase-catalyzed reaction and further refine the search for ODCase inhibitors.